Comparison of Omadacycline and Tigecycline Pharmacodynamics in the Plasma, Epithelial Lining Fluid, and Alveolar Macrophages in Healthy Subjects

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1 Comparison of Omadacycline and Tigecycline Pharmacodynamics in the Plasma, Epithelial Lining Fluid, and Alveolar Macrophages in Healthy Subjects Karolyn S. Horn, Mark H. Gotfried, Judith N. Steenbergen, Stephen Villano, Evan Tzanis, Lynne Garrity-Ryan, Surya Chitra, Amy Manley, S. Ken Tanaka, Keith A. Rodvold University of Illinois at Chicago, Pulmonary Associates, and Paratek Pharmaceuticals, Inc.

2 Disclosures This study was funded by Paratek Pharmaceuticals KAR has been a consultant to Paratek Pharmaceuticals JNS, SV, ET, LGR, SC, AM, and SKT are employees of Paratek Pharmaceuticals

3 Introduction Omadacycline (PTK 0796) is a first-in-class aminomethylcycline antibiotic Chemical structure overcomes efflux pump and ribosomal protection mechanisms of tetracycline resistance In vitro activity against respiratory pathogens including: Methicillin-resistant Staphylococcus aureus (MRSA) Multidrug-resistant Streptococcus pneumoniae Haemophilus influenzae, Moraxella catarrhalis Legionella pneumophila, Chlamydophila pneumoniae, Mycoplasma pneumoniae Omadacycline was recently shown to be noninferior to moxifloxacin in a Phase 3 clinical trial for community-acquired bacterial pneumonia (CABP) [NCT ] Future Microbiol. 2016; 11:

4 Intrapulmonary Sites and Pharmacodynamics Epithelial lining fluid (ELF) and alveolar cells (AC) have been advocated as important infection sites for common extracellular and intracellular respiratory pathogens, respectively Ratio of AUC 0-24 to MIC (AUC 0-24 /MIC) has been the pharmacokineticpharmacodynamic parameter that best correlates with antibacterial efficacy for the tetracycline class of antibiotics Lepak et al. recently confirmed this for omadacycline against isolates of Streptococcus pneumoniae in a neutropenic mouse pneumonia model Typical ranges of ELF AUC 0-24 /MIC ratios associated with a net bacterial stasis and a 1-log and 2-log CFU reduction from baseline were to 17.80, 6.00 to 17.61, and to 47.27, respectively Clin Pharmacokinet 2011; 50: Antimicrob Agents Chemother 2017 Feb 13. pii: AAC

5 Objectives To determine concentrations of omadacycline and tigecycline in epithelial lining fluid (ELF) and alveolar cells (AC) and define the time course of pulmonary distribution with concurrent plasma sampling of omadacycline and tigecycline in healthy adult subjects To determine and compare the pharmacokinetics of omadacycline and tigecycline in plasma and pulmonary compartments in healthy adult subjects Compare AUC 0-24 /MIC ratios for omadacycline and tigecycline against common respiratory pathogens in the plasma, ELF, and AC

6 Methods Single center, multiple dose, open label study in healthy subjects years old No significant past medical history No concomitant medications Non-smokers Randomized to omadacycline or tigecycline Conducted according to Good Clinical Practice and Good Laboratory Practice guidelines

7 Methods Omadacycline (OMC) 100 mg intravenously q12h x 2 doses, then 100 mg q24h x 3 doses Tigecycline (TGC) 100 mg intravenously x 1 dose, then 50 mg q12h x 6 doses a Plasma: 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 h after the start of the 5 th dose Plasma: 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 h after the start of the 7 th dose 42 subjects randomized to 1 BAL time following the 5 th dose: 0.5, 1, 2, 4, 8, 12, or 24 h 21 subjects randomized to 1 BAL time following the 7 th dose: 2, 4, 6, 12 h Plasma and BAL samples were assayed for urea concentration and OMC or TGC concentrations (in plasma, BAL fluid, and cell pellet) using LC/MS/MS a Conte JE Jr, et al. Int J Antimicrob Agents 2005;25:

8 Methods Noncompartmental analysis of omadacycline and tigecycline in the plasma was performed using Phoenix WinNonlin, version 7.0 (Pharsight Corp., Cary, North Carolina) Plasma pharmacokinetic parameters were calculated using serial plasma concentration-time data obtained after the 5 th dose of omadacycline and 7 th dose of tigecycline AUC 0-24 for omadacycline and AUC 0-12 for tigecycline reported for plasma, ELF, and AC using linear-log trapezoidal method Calculations of the volume of ELF and drug concentration were determined with the urea dilution method Calculations of drug concentration in AC determined from measured concentration of drug and volume of AC in cell suspension

9 Results Enrollment 63 healthy subjects enrolled and received at least 1 dose of OMC or TGC 42 randomized to OMC 21 randomized to TGC 1 subject with BAL sampling error 2 subjects d/c due to TEAEs 2 subjects with dosing errors 41 subjects included in PK analysis for OMC 17 subjects included in PK analysis for TGC

10 Characteristics of Healthy Subjects Receiving Omadacycline and Tigecycline a Treatment Sex (n) Age (yr) Height (cm) Weight (kg) CL CR b (ml/min) BAL total cell count (cells/mm 3 ) Macrophages (%) Omadacycline Tigecycline M (28) F (13) M (13) F (4) a Data expressed as mean + SD except for sex (M = male, F = female) b CL CR calculated creatinine clearance using the Cockcroft-Gault formula

11 Plasma Pharmacokinetics Parameter a Omadacycline Tigecycline C max (mg/l) 2.12 ± ± 0.21 C min (mg/l) 0.28 ± ± 0.03 AUC 0- (mg h/l) ± ± 0.42 V ss (L) 190 ± ± 67 CL (L/h) 8.79 ± ± 4.1 t 1/2 (h) 16.0 ± ± 2.6 a Data expressed as mean ± SD

12 Mean (± SD) Total Plasma, ELF, and AC Concentrations During the BAL Sampling Times for Omadacycline and Tigecycline Omadacycline Tigecycline Site AUC 0- (mg h/l) Omadacycline Tigecycline AC Plasma ELF AC AC AUC Ratios: Site-to-Plasma ELF Site Omadacycline Tigecycline Plasma ELF Plasma Total P ELF:P AC:P Unbound P ELF:P AC:P a Villano S, et al. Poster 518. ASM Microbe b Mukker JK, et al. J Pharm Sci 2014;103: Plasma (P) protein binding: Omadacyclilne ~20% a Tigecycline ~ 72% b

13 AUC 0-24 / MIC 90 for ELF for Omadacycline and Tigecycline Against Extracellular Respiratory Tract Pathogens MIC 90 (mg/l) a AUC 0-24 / MIC 90 b Pathogen Omadacycline Tigecycline Omadacycline Tigecycline Streptococcus pneumoniae Staphylococcus aureus MSSA MRSA Moraxella catarrhalis Haemophilus influenzae a JMI 2016 Surveillance Data (on file, Paratek) b Based on mean AUC 0-24 in ELF: Omadacycline = mg h/l; Tigecycline = 6.32 mg h/l (2 AUC 0-12 )

14 AUC 0-24 / MIC 90 for AC for Omadacycline and Tigecycline Against Intracellular Respiratory Tract Pathogens MIC 90 (mg/l) a AUC 0-24 / MIC 90 b Pathogen Omadacycline Tigecycline Omadacycline Tigecycline Legionella pneumophila Chlamydophila pneumoniae Mycoplasma pneumoniae c a Dubois J et al. Poster 1992, ICAAC 2015; Edelstein PH et al. Antimicrob Agents Chemother 2003;47: ; JMI 2016 Surveillance Data (on file, Paratek) b Based on mean AUC 0-24 in AC: Omadacycline = 302 mg h/l; Tigecycline = 77 mg h/l (2 AUC 0-12 ) c Range <0.015 to 0.12 (only 8 strains)

15 Safety Omadacycline (N=42) Tigecycline (N=21) Subjects with any TEAE n (%) 12 (28.6) 11 (52.4) Headache 5 (11.9) 3 (14.3) TEAEs reported in > 1 subject Epistaxis 2 (4.8) 2 (9.5) Nausea 1 (2.4) 10 (47.6) Vomiting 0 3 (14.3) Decreased appetite 0 2 (9.5) Subjects with any TEAE leading to study drug discontinuation 0 2 (9.5) Nausea 0 2 (9.5) Subjects with any serious TEAE 0 0 There were no clinically significant findings in clinical laboratory results, vital signs or ECGs Further details were previously presented: Poster P1257, ECCMID 2017

16 Summary A similar pattern and time course of omadacycline and tigecycline was observed in plasma (total), ELF, and AC concentrations Despite having similar penetration ratios, the magnitude of systemic exposure (based of AUC 0-24 values) of omadacycline was approximately ~3-fold higher than tigecycline in plasma (total), ELF, and AC concentrations Higher concentrations allow for similar or greater AUC 0-24 /MIC at all sites evaluated for both extracellular and intracellular respiratory pathogens The intrapulmonary pharmacokinetics of omadacycline in healthy subjects suggests adequate target-site penetration for the current intravenous dosing regimen used in the clinical trial for community-acquired bacterial pneumonia Further analysis using larger omadacycline concentration-time and MIC datasets, population pharmacokinetic modeling, and Monte Carlo simulations are planned